‘Full fusion’ is not ineluctable during vesicular exocytosis of neurotransmitters by endocrine cells

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‘Full fusion’ is not ineluctable during vesicular exocytosis of neurotransmitters by endocrine cells, Proc. R. Soc. A 473: 20160684.

 

The significance of vesicular exocytosis in biology and medicine is evidenced, among many other examples, by two recent Nobel Prizes in Physiology and Medicine, the latest one being awarded in 2013 to James E. Rothman, RandyW. Schekman and Thomas C. Südhof. In neurons and endocrine cells neurotransmitters are transported as cargo by vesicles, tailored and loaded in the Golgi apparatus and delivered at specific release sites of the cell membrane where they dock to finally release neurotransmitters through a fusion pore connecting the cell and vesicle membranes. In endocrine cells, release through the initial fusion pore is minute and the pore may close or flicker (Kiss and Run), as occurs in neurons ; however, generally the pore rapidly expands to release a massive flux of neurotransmitters that is precisely quantifiable by amperometry at carbon-fibre micro- and nanoelectrodes. This stage is generally considered to end in the full integration of the vesiclemembrane into the cell membrane, hence its ‘full fusion’ designation. There is a wealth of data characterizing in deep detail vesicle formation and transport, SNARE-assisted docking stages as well as the initial fusion pore size and flickering dynamics. However, the ineluctability of the ‘full fusion’ stage has recently become a matter of debate, though, at least in endocrine cells, it conditions the ultimate purpose of the whole process leading to the release of neurotransmitters.

 

 

Altogether, the data presented here provide the first quantitative support for a new paradigm and reject the ineluctability of a ‘full fusion’ outcome when the fusion pore enlarges beyond its SNARE-stabilized architecture. If the rapid expansion of the fusion pore is unquestionably promoted by the viscous dissipation of the edge and surface tension energies of the vesicle–cell membrane assembly, the corresponding driving forces are rapidly counteracted by other forces that apply as soon as the fusion pore radius reaches approximately 15–30nm. Within this perspective, the occurrence of the much wider fusion pores observed by TIRFM or EM, a fact that usually substantiates the ‘full fusion’ paradigm, may be featuring either incidental rare events or exocytotic vesicle functions that are not related to neurotransmitter release but possibly to another role such as hormonal peptide regulation.

 

Consultez le communiqué de presse associé à cet article, rédigé par l'Institut de Chimie du CNRS : Libération des neurotransmetteurs : une nouvelle porte s’ouvre

 

 

Résumé: 

Proc. R. Soc. A 473: 20160684.

 

Vesicular exocytosis is an essential and ubiquitous process in neurons and endocrine cells by which neurotransmitters are released in synaptic clefts or extracellular fluids. It involves the fusion of a vesicle loaded with chemical messengers with the cell membrane through a nanometric fusion pore. In endocrine cells, unless it closes after some flickering (‘Kiss-and-Run’ events), this initial pore is supposed to expand exponentially, leading to a full integration of the vesicle membrane into the cell membrane—a stage called ‘full fusion’.We report here a compact analytical formulation that allows precise measurements of the fusion pore expansion extent and rate to be extracted from individual amperometric spike time courses. These data definitively establish that, during release of catecholamines, fusion pores enlarge at most to approximately one-fifth of the radius of their parent vesicle, hence ruling out the ineluctability of ‘full fusion’.

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‘Full fusion’ is not ineluctable during vesicular exocytosis of neurotransmitters by endocrine cells

 

Alexander Oleinick, Irina Svir and Christian Amatore

 

Proc. R. Soc. A 473: 20160684.

 

Doi : 10.1098/rspa.2016.0684